There are numerous viral infections which can be treated with various nucleosides. These infections include infections by the human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus, human cytomegalovirus (HCMV), Herpes Simplex I virus (HSV-1), Herpes Simplex virus type-2 (HSV-2), and Varicella Zoster virus (VZV).
Hepatitis B virus (HBV) is a causative agent of acute and chronic hepatitis. HBV infections are the world's ninth leading cause of death. HBV infection often leads to acute hepatitis and liver damage, and causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive form of the disease in which massive sections of the liver are destroyed. Many patients recover from acute viral hepatitis, but certain other patients have high levels of viral antigen which persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Chronic persistent hepatitis can cause fatigue, liver damage, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer. The epidemiology of HBV is in fact very similar to that of acquired immunodeficiency syndrome. Accordingly, HBV infection is common among patients with AIDS or HIV-associated infections. However, HBV is more contagious than HIV.
HBV infection is an increasingly serious problem among the homo- and heterosexual population, intravenous drug users, organ transplant recipients, and blood transfusion patients. New infection with HBV can be prevented by vaccination. However, the present vaccination is not effective for the approximately 350 million chronic carriers worldwide. It has been observed that suppression or eradication of the replication of HBV in the liver leads to improved liver pathology and decreased progression to liver cirrhosis and hepatocellular carcinoma.
The current therapy approved in the United States for treating chronic hepatitis B infection is alpha interferon, which is far from ideal. According to the American Liver Foundation and the International Hepatitis Foundation, patients with conditions such as advanced hepatitis, HIV coinfection, drug abuse or others are not eligible for this treatment, resulting in less than 50% of chronic carriers obtaining this therapy. Of these patients, only about 40% respond to the treatment. Many of these patients also relapse after treatment is stopped, and only about 30% of the patients show a long term benefit. Viral disappearance is only seen in about 10-20% of the treated patients. These data suggest that there is an extremely low response rate in patients treated with alpha interferon. In addition to the low response rate, interferon therapy causes severe side effects such as insomnia, depression, nausea, vomiting, fever and fatigue.
Various nucleosides have also been proposed for use in treating HBV infection. For example, lamivudine (3-TC) is approved; however, virus flare following therapy and increased emergence of resistant viral strains against lamivudine have been recognized in clinical trials with prolonged monotherapy in transplantation and chronic hepatitis patients. In the area of HBV, there is an urgent need to complement existing therapies (for example, with lamivudine) with other therapeutic agents. Accordingly, design and development of new anti-HBV chemotherapeutic agents, for use alone or in combination with other anti-HBV agents, is urgently needed for the management and treatment of chronic HBV infections.
Similar to hepatitis B virus, human immunodeficiency is a retrovirus. Although a number of nucleoside agents are known for HIV, they all don't show activity against hepatitis B virus (REF).
The Epstein-Barr virus (EBV) is a member of the genus Lymphocryptovirus, which belongs to the subfamily gammaherpesviridae. It is notably lymphotropic. EBV has the classic structure of herpes viruses, that is, its double-stranded DNA genome is contained within an icosapentahedral nucleocapsid, which, in turn, is surrounded by a lipid envelope studded with viral glycoproteins. An amorphous tegument protein occupies the space between the envelope and the nucleocapsid.
Human herpes viruses infect and replicate within lymphocytes to some extent, but EBV does so efficiently. Most importantly, the pathogenesis and host responses to infection with EBV are more dependent upon lymphocytic infection than is evident with the other human herpes viruses. EBV is now recognized as a cause of B-cell lymphoproliferative diseases, and has been linked to a variety of other severe and chronic illnesses, including a rare progressive mononucleosis-like syndrome and oral hairy leukoplakia in ADS patients. EBV DNA has been found in some T-cell lymphomas and Hodgkin's tissue samples. EBV has also been associated with autoimmune diseases such as Sjogren's syndrome.
EBV is primarily transmitted through the saliva, although some infections are transmitted by blood transfusion. More than 85% of patients in the acute phases of infectious mononucleosis secrete EBV.
EBV has been associated with cancer. At least two groups of patients are at risk for development of EBV-associated lymphomas: those who have received transplants of kidney, heart, bone marrow, liver, or thymus under the cover of immunosuppressive therapy, and patients with AIDS. EBV-associated cancers include Burkitt's Lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma and Nasopharyngeal Carcinoma.
Several different DNA viruses have been shown to cause tumors in animals. The effect of cancerogenic chemicals on animals can result in activation of latent tumor viruses. It is possible that tumor viruses are involved in human tumors. The most likely human cases known today are leukemias, sarcomas, breast carcinomas, and cervical cancers where herpes viruses are also indicated. This makes the search for selective inhibitors of tumorigenic viruses and their functions an important undertaking in efforts to treat cancers.
There remains a strong need to provide new effective pharmaceutical agents to treat humans infected with herpes-viruses such as EBV. So far there is no effective drug for the treatment of EBV infections.
A variety of nucleosides are known as biologically important nucleosides, and a number of other nucleosides are known as intermediates for preparing these nucleosides. For example, cyclonucleosides have been used as intermediates for preparing halopyrimidine nucleosides. Lipshutz et al., Synthesis, 1476-1484 (1994), discloses forming diastereomeric cyclonucleosides (wherein the C-5′-hydroxyl group is coupled to a pyrimidine base such as thymine to form an ether linkage) as an intermediate for forming certain pyrimidine nucleosides. However, Lipshutz does not disclose or suggest the anti-Epstein Barr virus or anti-hepatitis B virus activity of the cyclonucleosides. Cadet et al., 109(21):6715-6720 (1978), discloses forming cyclic pyrimidine nucleosides as by-products in the irradiation of uracil derivatives. Sako et al., Synthesis, 829-831 (1987), also discloses using cyclonucleosides as intermediates for synthesizing partially modified nucleosides and nucleotides. Maruyama et al., J. Org. Chem., 48:2719-2723 (1983), discloses halogenating pyrimidine 5′-C6-cyclonucleosides to form halopyrimidine nucleosides. Although the halopyrimidine nucleosides are known to be biologically active as antiviral and antitumor agents, the antiviral (Epstein Barr virus, hepatitis B virus) ability of the 5′-C6-cyclonucleosides is neither disclosed nor suggested.
Some of 5,6-dihydro pyrimidine nucleosides are known to possess activity against human immunodeficiency virus, however, the hepatitis B virus and Epstein B virus activity have not been described before. Similarly, acyclic pyrimidine nucleosides have not been shown to possess activity against hepatitis B virus.
Accordingly, it is an object of the present invention to provide compounds and methods for treating viral infections caused by exposure to herpes viruses such as Epstein Barr virus, and Hepatitis B virus. The present invention provides such compounds and methods.